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FEMS Microbiology Reviews Nov 2014The presence of an abnormal amount of single-stranded DNA in the bacterial cell constitutes a genotoxic alarm signal that induces the SOS response, a broad regulatory... (Review)
Review
The presence of an abnormal amount of single-stranded DNA in the bacterial cell constitutes a genotoxic alarm signal that induces the SOS response, a broad regulatory network found in most bacterial species to address DNA damage. The aim of this review was to point out that beyond being a repair process, SOS induction leads to a very strong but transient response to genotoxic stress, during which bacteria can rearrange and mutate their genome, induce several phenotypic changes through differential regulation of genes, and sometimes acquire characteristics that potentiate bacterial survival and adaptation to changing environments. We review here the causes and consequences of SOS induction, but also how this response can be modulated under various circumstances and how it is connected to the network of other important stress responses. In the first section, we review articles describing the induction of the SOS response at the molecular level. The second section discusses consequences of this induction in terms of DNA repair, changes in the genome and gene expression, and sharing of genomic information, with their effects on the bacteria's life and evolution. The third section is about the fine tuning of this response to fit with the bacteria's 'needs'. Finally, we discuss recent findings linking the SOS response to other stress responses. Under these perspectives, SOS can be perceived as a powerful bacterial strategy against aggressions.
Topics: Bacteria; DNA Repair; Gene Expression Regulation, Bacterial; SOS Response, Genetics; Stress, Physiological
PubMed: 24923554
DOI: 10.1111/1574-6976.12077 -
International Journal of Molecular... Jun 2018
Topics: Animals; DNA Damage; DNA Repair; DNA Replication; Disease; Genome, Human; Humans; Phosphorylation
PubMed: 29958460
DOI: 10.3390/ijms19071902 -
International Journal of Molecular... Sep 2020Precise gene editing is-or will soon be-in clinical use for several diseases, and more applications are under development. The programmable nuclease Cas9, directed by a... (Review)
Review
Precise gene editing is-or will soon be-in clinical use for several diseases, and more applications are under development. The programmable nuclease Cas9, directed by a single-guide RNA (sgRNA), can introduce double-strand breaks (DSBs) in target sites of genomic DNA, which constitutes the initial step of gene editing using this novel technology. In mammals, two pathways dominate the repair of the DSBs-nonhomologous end joining (NHEJ) and homology-directed repair (HDR)-and the outcome of gene editing mainly depends on the choice between these two repair pathways. Although HDR is attractive for its high fidelity, the choice of repair pathway is biased in a biological context. Mammalian cells preferentially employ NHEJ over HDR through several mechanisms: NHEJ is active throughout the cell cycle, whereas HDR is restricted to S/G2 phases; NHEJ is faster than HDR; and NHEJ suppresses the HDR process. This suggests that definitive control of outcome of the programmed DNA lesioning could be achieved through manipulating the choice of cellular repair pathway. In this review, we summarize the DSB repair pathways, the mechanisms involved in choice selection based on DNA resection, and make progress in the research investigating strategies that favor Cas9-mediated HDR based on the manipulation of repair pathway choice to increase the frequency of HDR in mammalian cells. The remaining problems in improving HDR efficiency are also discussed. This review should facilitate the development of CRISPR/Cas9 technology to achieve more precise gene editing.
Topics: Animals; CRISPR-Cas Systems; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Endonucleases; Gene Editing; Humans; RNA, Guide, CRISPR-Cas Systems; Recombinational DNA Repair
PubMed: 32899704
DOI: 10.3390/ijms21186461 -
Nature Cell Biology Jul 2023Proper repair of DNA damage lesions is essential to maintaining genome integrity and preventing the development of human diseases, including cancer. Increasing evidence...
Proper repair of DNA damage lesions is essential to maintaining genome integrity and preventing the development of human diseases, including cancer. Increasing evidence suggests the importance of the nuclear envelope in the spatial regulation of DNA repair, although the mechanisms of such regulatory processes remain poorly defined. Through a genome-wide synthetic viability screen for PARP-inhibitor resistance using an inducible CRISPR-Cas9 platform and BRCA1-deficient breast cancer cells, we identified a transmembrane nuclease (renamed NUMEN) that could facilitate compartmentalized and non-homologous end joining-dependent repair of double-stranded DNA breaks at the nuclear periphery. Collectively, our data demonstrate that NUMEN generates short 5' overhangs through its endonuclease and 3'→5' exonuclease activities, promotes the repair of DNA lesions-including heterochromatic lamina-associated domain breaks as well as deprotected telomeres-and functions as a downstream effector of DNA-dependent protein kinase catalytic subunit. These findings underline the role of NUMEN as a key player in DNA repair pathway choice and genome-stability maintenance, and have implications for ongoing research into the development and treatment of genome instability disorders.
Topics: Humans; DNA Repair; DNA Breaks, Double-Stranded; DNA-Binding Proteins; DNA End-Joining Repair; Endonucleases
PubMed: 37322289
DOI: 10.1038/s41556-023-01165-1 -
Molecular Cell May 2023Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous...
Microhomology-mediated end joining (MMEJ) is an intrinsically mutagenic pathway of DNA double-strand break (DSB) repair essential for proliferation of homologous recombination (HR)-deficient tumors. Although targeting MMEJ has emerged as a powerful strategy to eliminate HR-deficient (HRD) cancers, this is limited by an incomplete understanding of the mechanism and factors required for MMEJ repair. Here, we identify the APE2 nuclease as an MMEJ effector. We show that loss of APE2 inhibits MMEJ at deprotected telomeres and at intra-chromosomal DSBs and is epistatic with Pol Theta for MMEJ activity. Mechanistically, we demonstrate that APE2 possesses intrinsic flap-cleaving activity, that its MMEJ function in cells depends on its nuclease activity, and further identify an uncharacterized domain required for its recruitment to DSBs. We conclude that this previously unappreciated role of APE2 in MMEJ contributes to the addiction of HRD cells to APE2, which could be exploited in the treatment of cancer.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA; DNA End-Joining Repair; Homologous Recombination
PubMed: 37044098
DOI: 10.1016/j.molcel.2023.03.017 -
International Journal of Molecular... Jan 2017
Topics: Animals; DNA Damage; DNA Repair; Diet; Disease; Epigenesis, Genetic; Humans; Oxidative Stress
PubMed: 28275213
DOI: 10.3390/ijms18010166 -
Seminars in Cell & Developmental Biology Mar 2022Chromothripsis is a unique form of genome instability characterized by tens to hundreds of DNA double-strand breaks on one or very few chromosomes, followed by... (Review)
Review
Chromothripsis is a unique form of genome instability characterized by tens to hundreds of DNA double-strand breaks on one or very few chromosomes, followed by error-prone repair. The derivative chromosome(s) display massive rearrangements, which lead to the loss of tumor suppressor function and to the activation of oncogenes. Chromothripsis plays a major role in cancer as well as in other conditions, such as congenital diseases. In this review, we discuss the repair processes involved in the rejoining of the chromosome fragments, the role of DNA repair and checkpoint defects as a cause for chromothripsis as well as DNA repair defects resulting from chromothripsis. Finally, we consider clinical implications and potential therapeutic vulnerabilities that could be utilized to eliminate tumor cells with chromothripsis.
Topics: Chromothripsis; DNA Breaks, Double-Stranded; DNA Repair; Gene Rearrangement; Genomic Instability; Humans
PubMed: 33589336
DOI: 10.1016/j.semcdb.2021.02.001 -
Blood Jun 2022
Topics: Chromatin Assembly and Disassembly; DNA Repair; Epigenesis, Genetic; Epigenome
PubMed: 35679076
DOI: 10.1182/blood.2022016176 -
Mutation Research May 2018
Topics: Animals; DNA Damage; DNA Repair; DNA Replication; Humans; Recombination, Genetic
PubMed: 29728263
DOI: 10.1016/j.mrfmmm.2018.04.002 -
International Journal of Molecular... Feb 2021DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous... (Review)
Review
DNA double-strand breaks (DSBs) are among the most serious forms of DNA damage. In humans, DSBs are repaired mainly by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). Single-strand annealing (SSA), another DSB repair system, uses homologous repeats flanking a DSB to join DNA ends and is error-prone, as it removes DNA fragments between repeats along with one repeat. Many DNA deletions observed in cancer cells display homology at breakpoint junctions, suggesting the involvement of SSA. When multiple DSBs occur in different chromosomes, SSA may result in chromosomal translocations, essential in the pathogenesis of many cancers. Inhibition of RAD52 (RAD52 Homolog, DNA Repair Protein), the master regulator of SSA, results in decreased proliferation of BRCA1/2 (BRCA1/2 DNA Repair Associated)-deficient cells, occurring in many hereditary breast and ovarian cancer cases. Therefore, RAD52 may be targeted in synthetic lethality in cancer. SSA may modulate the response to platinum-based anticancer drugs and radiation. SSA may increase the efficacy of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR associated 9) genome editing and reduce its off-target effect. Several basic problems associated with SSA, including its evolutionary role, interplay with HRR and NHEJ and should be addressed to better understand its role in cancer pathogenesis and therapy.
Topics: BRCA1 Protein; BRCA2 Protein; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Breaks, Double-Stranded; DNA Repair; DNA, Single-Stranded; Female; Gene Editing; Genomic Instability; Humans; Neoplasms
PubMed: 33671579
DOI: 10.3390/ijms22042167